Skin is the most visible indicator of the aging process. The overall focus of this proposal is to understand the mechanisms that underlie cell survival and aging in the epidermis of skin. The mammalian epidermis is in equilibrium, as mitotically, the following questions are addressed: (1) Do epidermal keratinocytes that overexpress cell survival factors in transgenic mice display a prolonged proliferative capacity? Does expression of cell survival factors in skin decline with age? (2) Do transgenic epidermal cells overexpressing cell survival factors express an increased level of beta1 integrin (a protein recently shown to be expressed at higher levels in epidermal stem cells)? (3) How does the level of beta1 expression vary with age in control skin, and is there a correlation between the levels of beta expression and decline in proliferative capacity with aging? (4) In the normal population of mitotically active keratinocytes, do those cells that express higher levels of beta1 integrin also express elevated levels of cell survival factors? (5) Do transgenic mice expressing elevated levels of beta1 integrin in their basal layer have a prolonged proliferative capacity, and are they more resistant to UV damage-induced apoptosis? Do they have elevated levels of cell survival factors? (6) Is expression of cadherin- associated proteins altered in Bcl-x and/or beta1 integrin expressing transgenic mice, and does it change with age in normal skin? Do differences correlate with proliferative capacity? This research is a fundamental prerequisite to our global understanding of the molecular mechanisms that controls aging, a process that inevitably affects us all.